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Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3‐only Bcl‐2 family member Bim
Author(s) -
Akiyama Toru,
Bouillet Phillippe,
Miyazaki Tsuyoshi,
Kadono Yuho,
Chikuda Hirotaka,
Chung Ungil,
Fukuda Akira,
Hikita Atsuhiko,
Seto Hiroaki,
Okada Takashi,
Inaba Toshiya,
Sanjay Archana,
Baron Roland,
Kawaguchi Hiroshi,
Oda Hiromi,
Nakamura Kozo,
Strasser Andreas,
Tanaka Sakae
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg635
Subject(s) - biology , osteoclast , apoptosis , ubiquitin , microbiology and biotechnology , bcl 2 family , family member , puma , genetics , cancer research , programmed cell death , gene , in vitro , medicine , family medicine
Osteoclasts (OCs) undergo rapid apoptosis without trophic factors, such as macrophage colony‐stimulating factor (M‐CSF). Their apoptosis was associated with a rapid and sustained increase in the pro‐apoptotic BH3‐only Bcl‐2 family member Bim. This was caused by the reduced ubiquitylation and proteasomal degradation of Bim that is mediated by c‐Cbl. Although the number of OCs was increased in the skeletal tissues of bim−/− mice, the mice exhibited mild osteosclerosis due to reduced bone resorption. OCs differentiated from bone marrow cells of bim−/− animals showed a marked prolongation of survival in the absence of M‐CSF, compared with bim+/+ OCs, but the bone‐resorbing activity of bim−/− OCs was significantly reduced. Overexpression of a degradation‐resistant lysine‐free Bim mutant in bim−/− cells abrogated the anti‐apoptotic effect of M‐CSF, while wild‐type Bim did not. These results demonstrate that ubiquitylation‐dependent regulation of Bim levels is critical for controlling apoptosis and activation of OCs.